Paternal Obesity, Interventions, and Mechanistic Pathways to Impaired Health in Offspring

Abstract

Background: The global rates of male overweight/obesity are rising, approaching 70% of the total adult population in Western nations. Overweight/obesity increases the risk of chronic diseases; however, there is increasing awareness that male obesity negatively impacts fertility, subsequent pregnancy, and the offspring health burden. Developmental programming is well defined in mothers; however, it is becoming increasingly evident that developmental programming can be paternally initiated and mediated through paternal obesity. Key Messages: Both human and rodent models have established that paternal obesity impairs sex hormones, basic sperm function, and molecular composition. This results in perturbed embryo development and health and an increased subsequent offspring disease burden in both sexes. The reversibility of obesity-induced parental programming has only recently received attention. Promising results in animal models utilizing diet and exercise interventions have shown improvements in sperm function and molecular composition, resulting in restorations of both embryo and fetal health and subsequent male offspring fertility. The direct mode for paternal inheritance is likely mediated via spermatozoa. We propose two main theories for the origin of male obesity-induced paternal programming: (1) accumulation of sperm DNA damage resulting in de novo mutations in the embryo and (2) changes in sperm epigenetic marks (microRNA, methylation, or acetylation) altering the access, transcription, and translation of paternally derived genes during early embryogenesis. Conclusions: Paternal overweight/obesity induces paternal programming of offspring phenotypes likely mediated through genetic and epigenetic changes in spermatozoa. These programmed changes to offspring health appear to be partially restored via diet/exercise interventions in obese fathers preconception, which have been shown to improve aspects of sperm DNA integrity. However, the majority of data surrounding paternal obesity and offspring phenotypes have come from rodent models; therefore, we contend that it will be increasingly important to study population-based data to determine the likely mode of inheritance in humans.

When two obese parents are worse than one! Impacts on embryo and fetal development

“…Because father-to-embryo transmission excludes gestational effects, mechanistically, imprinting, altered DNA methylation, histone modifications, and noncoding RNA changes in sperm or alterations to seminal plasma composition, which can influence the signaling of the female reproductive tract, have been implicated in paternal nongenetic transmission (9,53). In Drosophila, consumption of a high-sugar diet by fathers alters the chromatin state of metabolic dependent genes in offspring, which persisted into embryos and which were originally altered in sperm (68).…”

Paternal Programming of Liver Function and Lipid Profile Induced by a Paternal Pre-Conceptional Unhealthy Diet: Potential Association with Altered Gut Microbiome Composition

“…Several studies showed that also paternal nutritional factors, in particular during maturation of the sperm, may alter the epigenome and the phenotype of the offspring [27-30]. …”

Male birthweight, semen quality and birth outcomes

“…In animal studies, Sertoli cell development and, potentially, sperm production, are affected by maternal nutrition during pregnancy (Olsen et al, 2000;Genovese et al 2010). Paternal lifestyle, behavior and environmental exposure may impact offspring as well (McPherson et al, 2014;Soubry et al, 2014). However, evidence from epidemiologic studies of peri-conceptional effects on offspring reproductive function is limited and equivocal (Power et al, 2003;Dupont et al, 2012).…”